Management of Itch in Atopic Dermatitis Judith Hong, MD,* Joerg Buddenkotte, Phd,*,† Timothy G
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Management of Itch in Atopic Dermatitis Judith Hong, MD,* Joerg Buddenkotte, PhD,*,† Timothy G. Berger, MD,* and Martin Steinhoff, MD, PhD‡ Atopic dermatitis is a common, pruritic, inflammatory skin disorder. Chronic, localized, or even generalized pruritus is the diagnostic hallmark of atopic dermatitis, and its manage- ment remains a challenge for physicians. The threshold for itch and alloknesis is markedly reduced in these patients, and infections can promote exacerbation and thereby increase the itch. Modern management consists of anti-inflammatory, occasionally antiseptic, as well as antipruritic therapies to address the epidermal barrier as well as immunomodulation or infection. Mild forms of atopic dermatitis may be controlled with topical therapies, but moderate-to-severe forms often require a combination of systemic treatments consisting of antipruritic and immunosuppressive drugs, phototherapy, and topical compounds. In addi- tion, patient education and a therapeutic regimen to help the patient cope with the itch and eczema are important adjuvant strategies for optimized long-term management. This review highlights various topical, systemic, and complementary and alternative therapies, as well as provide a therapeutic ladder for optimized long-term control of itch in atopic dermatitis. Semin Cutan Med Surg 30:71-86 © 2011 Elsevier Inc. All rights reserved. ruritus or itch, which is defined as an unpleasant sensa- and focus in-depth on the various types of treatments for Ption that elicits an urge to scratch,1 is such an integral part short-term and long-term management of itch in AD. of atopic dermatitis (AD) that it is a major characteristic in the diagnostic criteria and a hallmark of AD.2 AD has been called the “itch that rashes,”3 which reflects how important it is to Pathophysiology of Itch in AD pay attention to pruritus in the management of AD. Pruritus The sensation of pruritus can be triggered by endogenous can lead patients to scratch until they are bleeding, and and exogenous stimuli, which activate specific peripheral un- scratching in turn can aggravate the skin disease. Nocturnal myelinated C-fiber nerve endings in the epidermis and der- scratching is a common issue that can result in sleep distur- mis. The pruritogenic stimulus is then signaled along the bances and a dramatic impairment in the quality of life in dorsal root ganglion (which harbors the RNA and generates these patients. In addition, psychological disturbances, such the proteins expressed by or released from the cell surface of as stigmatization and social isolation,4 are also detriments to nerve-endings) via the spinal cord before it crosses the con- quality of life.5 In this article we briefly summarize current tralateral spinothalamic tract, reaching different areas of the knowledge of the pathophysiology and trigger factors of AD cortex. In the cortex, the scratching reflex is initialized in the motor-cortex and associated motor-cortex. Other cortical and subcortical regions can modulate the itch response, lead- *Department of Dermatology, University of California San Francisco, San Francisco, CA. ing to “sensitized skin” and itch-associated mood changes, 6,7 †Department of Surgery, University of California San Francisco, San Fran- for example. Thus, the central nervous system modulates cisco, CA. the perception of “itch” and triggers the desire to scratch. ‡Department of Dermatology, University Hospital, Münster, Münster, Ger- Various mediators of pruritus in AD interact with the pruri- many. toception pathway at different levels. For example, in lamina Dr. Judith Hong, Dr. Joerg Buddenkotte and Dr. Timothy G. Berger have nothing to disclose. Dr. Steinhoff has performed consultancy services for 1 of the dorsal horn, the gastrin-releasing peptide receptor 8,9 which he received compensation for Galderma, Merck, Sanofi-Aventis plays a role in mediating itch sensation in the spinal cord. and Regeneron. On behalf of Dr. Steinhoff, his institution has received The receptor for substance P (SP), the neurokinin-1 receptor, financial gifts from Maruho (Japan), and research was supported by is also highly expressed by lamina 1 neurons, which appears ZymoGenetics, L’Oreal and Galderma. to be crucial for the transmission of itch to the brain.6 Cuta- Address reprint requests to Martin Steinhoff, MD, PhD, Departments of 10 11-13 Dermatology and Surgery, University of California San Francisco, 513 neous inductors of itch include histamine, proteases, 14,15 Parnassus Avenue, Room S-1268, San Francisco, CA, 94143. E-mail: neuropeptides (eg, SP), acetylcholine (in atopic pa- [email protected] tients),16 cytokines,17 neurotrophin-4,18 platelet-activating 1085-5629/11/$-see front matter © 2011 Elsevier Inc. All rights reserved. 71 doi:10.1016/j.sder.2011.05.002 72 J. Hong et al Table 1 Therapeutic Ladder for AD Associated Pruritus For Consideration but Second Line (or First Line Controversial and/or Treatment Category First Line in Severe Disease) Minimal Evidence Trigger elimination ● Avoiding exogenous ● Food allergen avoidance in ● Bacterial decolonization triggers (see Table 2) symptomatic patients ● Food allergen avoidance ● Antimicrobials for overt in asymptomatic secondary infection patients ● Stress management ● Dust-mite reduction Topical therapy ● Emollients ● Calcineurin inhibitors* ● Menthol ● Corticosteroids ● Coal tar ● Capsaicin ● Naltrexone ● Doxepin Systemic therapy ● Oral sedating antihistamines ● Other (minimal evidence in AD, but immunosuppressants soporific effect may be (eg, azathioprine, helpful) mycophenolate mofetil, ● Combination of nonsedating methotrexate, interferon- and sedating antihistamines gamma) (high-dose) ● Mu-opiate receptor ● Cyclosporine A antagonists ● Corticosteroids ● Kappa-opioid agonist ● Neurogenic agents (eg, gabapentin, mirtazapine, paroxetine) Other ● Education about disease ● Phototherapy (UVA, UVA1, ● Excimer laser and treatment modalities UVB, Combination, PUVA) ● Herbals and botanicals Written instructions and/or ● Goeckerman (phototherapy ؉ ● Hypnotherapy ● handouts in addition to tar) ● Massage verbal instructions ● Psychological interventions ● Biofeedback (eg, cognitive-behavioral ● Acupuncture therapy, habit reversal therapy, autogenic training) AD, atopic dermatitis. *May be also used as first line for maintenance therapy. factor,19 endothelin, and certain leukotrienes.20 Of note, pruritus on patient’s lives, dermatologists need to recognize changes in the plasticity and receptor density, as well as neu- and address various aspects of itch, including: (1) identifica- ronal sensitization, may also be involved in AD pruritus.21 tion and elimination of trigger factors; (2) maintaining the The skin lesions in AD often have increased density of pe- skin barrier through emollients and occasional additives; ripheral nerve fibers, including substance P-positive nerve (3) targeting inflammation through topical medications, fibers.22 In addition, noxious stimuli, such as bradykinin in systemic medications, or phototherapy; (4) symptomatic the lesional skin of AD patients, have been demonstrated to management of itch with other treatments that are not provoke itch instead of pain, suggesting complex but poorly antiinflammatory; (5) addressing psychological and be- understood interactions between itch and pain fibers.23-25 havioral components; and (6) educating the patient (Table TH2-derived cytokines may be involved in crosstalk between 1). The use of multidisciplinary clinics or centers will be nerves and T lymphocytes, indicating a role of cytokines in discussed in further detail because they provide a setting itch and neuronal regulation.6,26,27 For an in-depth study, we where all these issues can be addressed. It is important for refer to other recent reviews focusing on the pathophysiology clinicians to “treat the patient, not just the disease” through of itch in AD.28-30 an approach that integrates medication, education, and sup- port. Overview: Treatment Options in AD Identification and Elimination of Trigger Factors Because itch is such a prominent and distressing aspect of AD, proper treatment of AD should involve the evaluation Identifying and eliminating trigger factors are crucial for the and management of any associated pruritus. Because of the management of itch in AD. Sweating is generally considered complex pathophysiology of pruritus in AD and the impact of one of the most common trigger of itch in AD,31 and in- Pruritus therapy in atopic dermatitis 73 creased sweating has been observed in AD patients with li- Table 2 Trigger Factors in AD for Consideration in the Long- chenified skin.32 Acetylcholine and vasoactive intestinal pep- Term Management of AD tide may play a role because both regulate sweat gland Allergies House dust mites, food allergens, air-born function and have been found to be increased in the skin of contact dermatitis (pollen, etc), animals, AD patients.33 The main methods to manage this frequent jewelry. trigger factor are avoidance of activities that lead to pro- Infections Staphylococcus aureus, viral infections nounced sweating or immediate washing and cooling after (herpes, molluscum), yeasts (eg, exercising. Anticholinergic drugs do not appear to have an Trichophyton, malassezia). impact on pruritus and can be avoided,34 supporting the idea Exogenous Soaps, solvents, wool, sweat, chemicals, toxins, cigarette smog, certain that neuropeptides, such as vasoactive intestinal peptide and ingredients of cosmetics probably yet unknown mediators, are more important in trig- Physical